Cytoreductive surgery and hyperthermic intrapleural chemotherapy for ...

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Cytoreductive surgery and hyperthermic intrapleural chemotherapy for malignant pleural diseases: preliminary experience Marcello Migliore*,1, Damiano Calvo1, Alessandra Criscione1, Cristina Viola1, Giuseppe Privitera2, Corrado Spatola2, Hector Soto Parra3, Stefano Palmucci4, Nicola Ciancio5, Rosario Caltabiano6 & Giuseppe Di Maria5,7 Abstract Cytoreductive surgery and hyperthermic-intraoperative-intrapleuralchemotherapy (HITHOC) is a known approach for malignant pleural diseases (MPD). This study was started to clarify the role of cytoreductive surgery and HITHOC in MPD. Criteria of inclusion were early-stage disease in malignant pleural mesothelioma (MPM), young age, good condition and selected stage-M1a lung cancer. Six patients with MPM and two patients with lung cancer were enrolled. After surgical debulking, intrapleural cisplatin was administered for 60 min at 42.5°C. Wedge, rib resection and repaired diaphragm were added in three, one and one patient, respectively. Morbidity, toxicity and mortality was nil. Hospital stay was 8 days. Mean survival is 13.6 months. This experience confirms that cytoreductive surgery and HITHOC is a good option in the treatment of MPD. A randomized controlled trial is necessary. Malignant pleural disease (MPD) heralds a dismal survival of 6–9 months, whether it represents a primary or secondary (metastatic) neoplasm. While the most frequent primary pleural neoplasm is malignant pleural mesothelioma (MPM), lung cancer is the commonest cause of secondary pleural tumor. Literature is full of papers reporting surgical treatment for MPM, and most patients are treated with curative intent using pleurectomy, pleuropneumectomy or with simple talc pleurodesis as a palliative surgery [1–4] . Few authors reported Phase II study on the use of hyperthermic intraoperative intrathoracic chemotherapy (HITHOC) with satisfactory results [5,6] . On the contrary, scanty reports are available regarding cytoreduction surgery for secondary pleural tumor [7,8] , and surgery is not contemplated. We present preliminary data of our prospective experience initiated in October 2011 with MPD treated using citoreduction by video assisted thoracic surgery (VATS) approach and HITHOC.

Keywords

• advanced lung cancer • chemotherapy • cytoreductive surgery • HITHOC • hyperthermic perfusion • lung cancer • mesothelioma • multimodality treatment

Methods This prospective study started in October 2011. All patients with MPD have been evaluated for possible treatment. All patients underwent an accurate preoperative work-up including past medical history, liver and renal tests, respiratory function tests (RFT), ECG, eco-cardiography, chest x-ray. Disease staging was performed using CT, PET scan and scintigraphy. Criteria of inclusions in the study are showed Academic Thoracic Surgery Unit, A.O.U. Policlinico-Vittorio Emanuele, Department of Surgery, University of Catania, Catania, Italy Radiotherapy Unit, A.O.U. Policlinico-Vittorio Emanuele, University of Catania, Catania, Italy 3 Oncology Unit, A.O.U. Policlinico-Vittorio Emanuele, Catania, Italy 4 Radiology Unit, A.O.U. Policlinico-Vittorio Emanuele, University of Catania, Catania, Italy 5 Pneumology Unit, A.O.U. Policlinico-Vittorio Emanuele, Catania, Italy 6 Department of Pathology, University of Catania, Catania, Italy 7 Department of Clinical & Molecular Bio-Medicine, University of Catania, Catania, Italy *Author for correspondence: [email protected] 1 2

10.2217/FON.14.256 © 2015 Future Medicine Ltd

Future Oncol. (2015) 11(2s), 47–52

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Supplement Migliore, Calvo, Criscione et al. in Box 1. Tumor diagnosis must be hystologically or cytologically confirmed via CT guided biopsy, cytologic examination of the pleural fluid or VATS [9,10] and PET scan is necessary to rule out distant and occult metastasis. When surgery is planned, and after informed consent is obtained, a pre- and post-operative hydration is administered with intravenous fluids at 150 ml/h for 12 h prior to surgery to reduce renal and hematologic toxicity. Surgery is performed using a VATS approach and a mini thoracotomy of 6–8 cm spreading the ribs with a small retractor [10] . The goal is to obtain a macroscopic cytoreduction in order to remove as much as macroscopic diseases involving the parietal (Figure 1) and visceral pleura. After surgical cytoreduction of the tumor, two drains, apical and basal, are inserted in the chest as shown in Figure 1 and connected to the extracorporeal machine. A temperature sensor is inserted into the chest, and the chest closed. The temperature is set to 42.5°C and the intrapleural perfusion is started with 0.9% sodium chloride solution. When an intracavitary temperature of 42.5°C is reached, intrapleural cisplatin perfusion is started at the dose of 120 mg/m2 for 60 min. Three different samples (100 cc) of pleural fluid are collected: the first (sample 1) immediately after chest is open, the second at the end of surgery (sample 2) and the third after the hyperthermic intrapleural chemoperfusion (sample 3). A postoperative hydration is given to prevent renal complications in the postoperative 24 h. After surgical intervention a chest x-ray is performed in recovery room and the patient spent one night in the high dependence unit. Primary end points are complications and survival. An adjuvant work up integration chemotherapy and radiotherapy was scheduled within 6 weeks from surgery to all patients. Results We operated eight patients (Table 1) – six males and two female – with a mean age of 63.7 years Box 1. Criteria of inclusion. ●● Confirmed diagnosis of malignant pleural disease

●● Disease must be confined in the chest ●● Age 1.0 l and EF >40% EF: Ejection fraction; FEV: Forced expiratory volume in 1 s.

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(range: 54–77). Six patients had MPM (five epithelial and one biphasic), and two patients adenocarcinoma of the lung with pleural metastasis. Preoperative diagnosis was made by cytology of the pleural fluid in four patients, by histological examination of the pleural samples obtained by VATS in three patients and tru-cut in one patient. Right thorax was involved in five patients. Comorbidities were: diabetes and hypertension in three, myocardial ischemia in two, BPCO in six patients and chronic renal failure in one. All patients were PET positive only in the chest, but one patient had a positive spot in two homolateral ribs. Associated pulmonary resection was performed in four patients, diaphragmatic resection in one and ribs resection in one patient (both repaired with a mesh). No intraoperative complications or toxicity were recorded. Macroscopic complete resection was obtained in four of six patients. Mean hospital stay was 8 days (range: 6–10). Mesothelioma Five (83.3%) of six patients (one female, five males) had previous asbestos exposure. The mean age was 66.8 (range: 54–77). The tumor was right-sided in four patients. Epithelial mesothelioma was recorded in five patients (Figure 1), one was biphasic. In one patient two units of blood transfusion was necessary. Hospital stay was 7.8 days (range: 6–10). 30 days mortality was 0, and no complications were reported. The toxicity was nil. Only in one patient with chronic renal failure there was recorded an increase in the creatinine level at day 2. In two patients nausea and vomiting was reported at postoperative day 1 and 2, and antiemetic drug therapy was necessary. Two patients were transferred to ICU for 24 h, and then to the high dependency unit in the ward. Mean survival is 13.3 months (6–21 months), and five patients are alive at the time of writing. In five of six patients the sample 3 cytology was negative for neoplastic cells when compared with sample 1. Adenocarcinoma of the lung – M1a Two patients have been operated. The first patient was a 53-year-old woman with lung adenocarcinoma of the right upper lobe associated with homolateral pleural metastasis and malignant pleural effusion. PET showed no mediastinal node involvement or distant metastasis. Preoperative Stage was pT1bN0M1a. Talc pleurodesis was performed in another hospital. Because the young age and the good

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Cytoreductive surgery & hyperthermic intrapleural chemotherapy for malignant pleural diseases

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Figure 1. Right parietal pleura of a patient with malignant pleural mesothelioma. Whitish pleural plaque is visible.

performance status, and following discussion with the patient, her relatives and oncologists, we offered cytoreduction surgery associated with HITHOC. The patient and family accepted the risk, and a VATS wedge resection of the primary tumor in the right upper lobe, pleurectomy and HITHOC with cisplatin was performed, and was disharged on the 7th postoperative day. The patient was EGFR- gene mutation positive, and she underwent treatment with EGFR inhibitor. The patient is alive at 16 months postoperatively, and diseases free interval is 13 months. The second patient was a 54-year-old male with right chest adenocarcinoma of unknown origin diagnosed by VATS 8 months previously. A neoadjuvant chemotherapy was given to reduce the tumor. Chest CT-scan and PET-CT scan showed no distant metastasis. The presence of the disease confined within the right emithorax with erosion of the 9th and 10th ribs and of the 9th and 10th vertebral soma. The patient had performance status 1 and no comorbidities. Two ribs resection were included in the specimen. Postoperative radiotherapy was given. The patient is alive at 6 months.


Discussion Our study focuses on the use of HITHOC for surgical treatment of malignant pleural disease showing a null mortality and toxicity, and acceptable mobility. The rationale of using HITHOC after cytoreduction surgery is that by attempting to sterile microscopic residual disease after surgical resection, infusion of the chemotherapeutic agent into the cavity will lead to increased exposure of tumor cells adjacent to its surface, while systemic concentrations will remain below toxic levels due to the limited absorption of the drug from the cavity. To improve the efficacy of chemotherapy, it can be combined with hyperthermia. A recent study in vitro has evaluated the role of hyperthermia associated with chemotherapy perfusion in different cell lines, including also human mesothelioma cell lines [11] , and another study proved that under ex vivo hyperthermic conditions, cisplatin diffused into human lung tissue with a median penetration depth of approximately 3–4 mm. The penetration of cisplatin into lung tissue may affect the local therapy of residual tumor cells on the lung surface using hyperthermic

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Supplement Migliore, Calvo, Criscione et al. Table 1. Data of the eight operated patients. No.

Sex, age (years)

Pleural effusion

Preop TNM Surgery

Hospital Complications stay (days)

Histology

Survival (months)

1 2 3 4 5 6 7

M, 72 M, 59 M, 62 F, 54 M, 77 M, 73 M, 55

No Yes Yes No Yes No No

T2N0 T2N2 T2N0 IVM1a T1N0 T2N0 IVM1a

6 9 9 8 10 7 9

No No No No No No No

MPM (epithelioid) MPM (epithelioid) MPM (epithelioid) Adenocarcinoma lung MPM (epithelioid) MPM (epithelioid) Adenocarcinoma lung

6 (died) 24 (alive) 19 (alive) 18 (alive) 16 (alive) 13 (alive) 7 (alive)

8

F, 59

Yes

T2N0

6

Anemia

MPM (epithelioid)

6 (alive)

P/D P/D P/D WR P/D WR P/D P/D P/D rib resection, WR P/D WR

F: Female; M: Male; MPM: Malignant pleural mesothelioma; P/D: Pleurectomy decortication; WR: Wedge resection.

intrathoracic chemotherapy perfusion in patients with malignant pleural tumors [12] . Hyperthermic intraoperative intrathoracic chemoperfusion has been performed after debulking surgery for MPM, lung cancer, thymoma and recurrent ovarian cancer with satisfactory results [7,13–17] . Our initial experience includes eight patients, of those six with MPM, and two with adenocarcinoma of the lung. A limitation of our study is the sample size which is too small and therefore it will be difficult to find significant relationships from our data, as statistical tests normally require a larger sample size to ensure a representative distribution of the population. Mesothelioma The survival in MPM is dismal, and several factors can influence prognosis [18,19] . Moreover although the problem is known since at least 30 years, very few prospective randomized trial exist. The MARS trial was stopped because the results were unsatisfactory and pleuropneumonectomy was shown to be an harmful procedure for patients [1] . The results of this prospective paper have been recently supported by different authors via the Society of Thoracic Surgeons Database and meta-analyses [20–22] . Recently, the result of a prospective randomized trial did not proved that pleurectomy has a longer survival when compared with talc pleurodesis in patients with MPM (overall survival at 1 year was 52 vs 57%; p = 0.81); on the contrary pleurodesis has a lower rate of c omplications and shorter hospital stay [23] . A Phase II study was performed to evaluate morbidity, mortality and outcome of HITHOC with cisplatin for MPM and has shown a 26 months median survival with high-dose cisplatin and epithelial tumor histology. In 2013,

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it has been also demonstrated that the use of HITHOC in 72 patients with MPM has a longer interval to recurrence (27.1 vs 12.8 months) and overall survival (35.3 vs 22.8 months) when compared with 31 patients who did not received HITHOC [24] . Because it does not exist a recommended and widely accepted curative treatment for MPM, it appears evident that the less invasive approach should be performed to ensure at least a good postoperative quality of life. Moreover, adjuvant thoracic radiotherapy and chemotherapy have been applied in MPM in several series [24–26] , with no definitive results. It has demonstrated a role in reducing the rate of local recurrence, above all in case of positive surgical margins. For years the main problem was that decision making is often performed according to surgeon preference but without scientific evidence demonstrating that one procedure is better than another, in few words treatments remained and remain still uncertain. This has been confirmed by recent papers on this argument. Finally, we agree with the opinion that patients with MPM should be operated only within a well-designed study protocol [27,28] . Adenocarcinoma of the lung – M1a Non-small-cell lung cancer with malignant pleural effusion has a very poor survival of 6–9 months, surgical therapy is not recommended and chemotherapy and palliation are the standard of care. Nevertheless, the understanding that surgery for selected patients with M1a lung cancer might not prolong survival is not definitively explained, and the fact that there are few recent positive reports which are in opposition to the originally thoughts on this argument can serve to generate renewed interest in surgery for selected patients in stage IV


Cytoreductive surgery & hyperthermic intrapleural chemotherapy for malignant pleural diseases lung cancer. This renewed interest can also drive further evidence supporting the prolongation of survival time maintaining a good quality of life. The rationale of using cytoredution surgery and HITHOC is the same for MPM. Cytoredution surgery and HITHOC could improve local pleural control and overall survival for selected patients with NSCLC and pleural metastasis such as those with M1a lung cancer and malignant pleural effusion with the diseases confined within the homolateral chest with absence of N2 disease. Some authors reported satisfactory results after cytoreductive surgery combined with HITHOC in patients with advanced non-smallcell lung cancer [7,8] . Matsuzaki et al. performed HITHOC following resection of the lung primary tumor (no pleurectomy) in 11 consecutive patients with primary pulmonary adenocarcinoma and pleural effusions containing tumor cells but without distant metastasis. The median survival time for patients receiving the perfusion treatment was 20 months while the median survival time for the control group was 6 months [29] . Isik AF et al. performed cytoreduction and HITHOC in 19 patients with MPD. The year survival was 54.7% in the HITHOC group 1 while it was 0.6 and 0.8% in group 2 and in group 3, respectively (p < 0.01 and p < 0.05) [16] . We have also noted a recent interest in non palliative methods to treat patients with advanced NSCLC in order to prolong survival mantaining a good quality of life. A proposed trial of resecting the primary lung cancer via a wedge resection in stage IV disease has been recently published in abstract form [30] . Hyperthermic References 1

2

3

Treasure T, Lang-Lazdunski L, Waller D et al. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol. 12(8), 763–772 (2011). Sugarbaker DJ, Flores RM, Jaklitsch MT et al. Resection margin, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: result in 183 patients. J. Thorac. Cardiovasc. Surg. 117(1), 54–65 (1999). Rush V, Saltz L,, Venkatraman E, et al. A Phase II trial of pleurectomy/decortication


intrathoracic chemotherapy could therefore become an additional therapeutic option in the multimodal treatment of selected patients with stage IV NSCLC with pleural metastasis confined to the chest. Selection for surgery will be of paramount importance, and a randomized clinical trial between pleurodesis alone versus HITHOC is necessary to confirm the long-term survival and the quality of life [31] of patients with incurable disease. Conclusion Our preliminary study shows that cytoreductive surgery (pleurectomy/decortication) and intraoperative hyperthermic intrathoracic chemotherapy could represent a choice of treatment for malignant pleural mesothelioma and selected patients with lung cancer and pleural metastasis. A randomized clinical trial is needed. Acknowledgements The authors thank the Di Dio Family for their donation in Memory of Giuseppe, and Medtronic Acquamantis for their gracious support with the use of bipolar sealers feature innovative Transcollation® technology.

Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.

followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J. Clin. Oncol. 12(6), 1156–1163 (1994). 4

5

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Spaggiari, L., Marulli, G., Bovolato, P et al. Extrapleural pneumonectomy for malignant mesothelioma: an Italian multicenter retrospective study. Ann. Thorac. Surg. 97, 1859–1866 (2014). Tilleman TR, Richards WD, Zellos L et al. Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: a Phase II prospective study. J. Thorac. Cardiovasc. Surg. 138(2), 405–411 (2009).

6

Richards WG, Zellos L, Bueno R, et al. Phase I to II study of pleurectomy/ decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma. J. Clin. Oncol. 24(10), 1561–1567 (2006).

7

Kyaw MA, HU W. Effect of cytoreductive surgery combinedwith intraoperative intra-thoracic hyperthermic chemotherapy in patients with advanced non-small cell lung cancer. J. Cancer Res. Treat. 2(1), 1–5(2014).

8

Ried M, Hofmann HS. The treatment of pleural carcinosis with malignant pleural effusion. Dtsch. Arztebl. Int. 110(18), 313–318 (2013).

9

Migliore M. Efficacy and safety of singletrocar technique for minimally invasive

www.futuremedicine.com

51

Supplement Migliore, Calvo, Criscione et al. surgery of the chest in the treatment of noncomplex pleural disease. J. Thorac. Cardiovasc. Surg. 126(5), 1618–1623 (2003). 10 Migliore M, Deodato G. Thoracoscopic

surgery, video-thoracoscopic surgery, or VATS: a confusion in definition. Ann. Thorac. Surg. 69(6), 1990–2001 (1991). 11 Cameron RB, Hou D. Intraoperative

hyperthermic chemotherapy perfusion for malignant pleural mesothelioma: an in vitro evaluation. J. Thorac. Cardiovasc. Surg. 145(2), 496–504 (2013). 12 Ried, M., Lehle, K., Neu, R. et al. Assessment

of cisplatin concentration and depth of penetration in human lung tissue after hyperthermic exposure. Eur. J. Cardiothorac. Surg. doi: 10.1093/ejcts/ezu217 (2014) (Epub ahead of print). 13 Ried M, Potzger T, Braune N et al.

Cytoreductive surgery and hyperthermic intrathoracic chemotherapy perfusion for malignant pleural tumours: perioperative management and clinical experience. Eur. J. Cardiothorac. Surg. 43(4), 801–807 (2012). 14 de Bree E, van Ruth S, Baas P et al.

Cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy in patients with malignant pleural mesothelioma or pleural metastases of thymoma. Chest 121(2), 480–487 (2002). 15 Kodama K, Higashiyama M, Okami J et al.

Cytoreductive surgery and post-operative heated pleural chemotherapy for the management of pleural surface malignancy. Int. J. Hyperthermia 29(7), 653–662 (2013). 16 Işık AF, Sanlı M, Yılmaz M et al. Intrapleural

hyperthermic perfusion chemotherapy in

52

subjects with metastatic pleural malignancies. Respir. Med. 107(5), 762–767 (2013). 17 van Ruth S, Baas P, Haas RL, Rutgers EJ,

Verwaal VJ, Zoetmulder FA. Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy for stage I malignant pleural mesothelioma. Ann. Surg. Oncol. 10(2), 176–182 (2003). 18 Di Maria G, Ciancio N, Migliore M. Lung

cancer and pleural mesothelioma. In: Respiratory Epidemiology. Annesi-Maesano I, Lundbäck B, Viegi G (Eds). ERS Monograph, 48–60 (2014). 19 Mineo TC. Malignant pleural mesothelioma:

factors influencing the prognosis. Oncology 26, 1164–1175 (2014). 20 Rena O, Casadio C. Extrapleural

pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure. Lung Cancer 77(1), 151–155 (2012). 21 Cao C, Tian D, Park J. A systematic review

and meta-analyses of surgical treatments for malignant pleural mesothelioma. Lung Cancer 83, 240–245 (2014). 22 Burt, B M Cameron RB, Mollberg NM, et al.

Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality. J. Thorac. Cardiovasc. Surg. 148(1), 30–35 (2014). 23 Rintoul RC, Ritchie AJ, Edwards JG et al.

Efficacy and cost of video-assisted thoracoscopic partial pleurectomy versus talc pleurodesis in patients with malignant pleural mesothelioma (MesoVATS): an open-label, randomised, controlled trial. Lancet 384(9948), 1118–1127 (2014).


24 Sugarbaker DJ, Gill RR, Yeap, BYH et al.

Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection. J. Thorac. Cardiovasc. Surg. 145(4), 955–963 (2013). 25 Rusch VW, Rosenzweig K, Venkatraman E

et al. A Phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J. Thorac. Cardiovasc. Surg. 122, 788–795 (2001). 26 Baldini EH. External beam radiation therapy

for the treatment of pleural mesothelioma. Thorac. Surg. Clin. 14, 543–548 (2004). 27 Lee, YC Gary, . Surgical resection of

mesothelioma: an evidence free practice. Lancet 384(9948), 1080–1081 (2014). 28 Datta A, Treasure T. Surgery in the

treatment of malignant pleural mesothelioma: recruitment into trials should be the default position. Thorax 69(2), 194–119. (2014). 29 Matsuzaki Y, Edagawa M, Shimizu T et al.

Intrapleural hyperthermic perfusion with chemotherapy increases apoptosis in malignant pleuritis. Ann. Thorac. Surg. 78(5), 1769–1772 (2004). 30 Dawson A G, Baines C, Joshi V, O’Byrne KJ,

Waller DA. Excision of the primary in stage IV non-small cell lung cancer (NSCLC): a feasibility study. Lung Cancer 83, Abstract S78 (2014). 31 Welte T. Progress means change. Dtsch.

Arztebl. Int. 110(18), 311–312 (2013).
